Radioprotective agents are compounds that reduce the biological effects of radiation (for review, see e.g., Hall, Radiobiology for the Radiobiologist, Lippincott Williams & Wilkins, Philadelphia, Pa. [1994]). They may be administrated before and/or after radiation exposure and can protect the organism from radiation-induced lethality. Radioprotectors have been shown to operate by a variety of different mechanisms (for review, see e.g., Bump and Malaker (eds.), Radioprotectors: Chemical, Biological, and Clinical Perspectives, CRC Press, Washington, D.C. [1997]). These include their antioxidant properties (Weiss and Landauer, Ann. NY Acad. Sci., 899:44-60 [2000]), their estrogenic activity (Miernicki et al., Soc. Neurosci. Abstr., 16:1054 [1990]; and Patt et al., Amer. J. Physiol., 159:269-280 [1949]), and/or in some cases, their ability to inhibit protein kinase(s) involved in signal transduction (Liu et al., Oncogene, 19: 571-579[2000]).
A variety of antioxidant compounds has been shown to confer radiation protection. These range from the highly toxic aminothiols to the antioxidant vitamins. However, the majority of these compounds have side effects of varying severity. For example, sulfhydryl radioprotectors such as amifostine (See e.g. U.S. Pat. No. 5,994,409) are highly toxic to mammals and must be administered in the hospital setting. Adverse side effects associated with these compounds include nausea and vomiting, hypotension, hypocalcemia and drowsiness (Bienvenu et al., Adv. Exp. Med. Biol., 264:291-300 [1990]). Amifostine acts by scavenging free radicals (Murray, in Bump and Malaker, supra). Antioxidant vitamins (A, C, E and beta carotene) provide only minimal levels of radiation protection, have a very short window of protection, and if obtained from dietary sources, must be eaten in a variety of foods, since any single food source only has small levels of any vitamin (Weiss and Landauer, supra).
In addition, using presently used methods and compositions, it is necessary to administer single high doses of agents such as pharmaceuticals or other chemical additives by parenteral routes within a short time frame before or after the radiation or chemical insult (See e.g., Bump and Malaker, supra). Therefore, this precludes their use as a long-term prophylactic measure for use in protection against unanticipated radiation injury. Because of the short duration of action of most radioprotective agents, there has been a long and on-going search for agents that confer long lasting protection. Indeed, there remains a great need for a nontoxic, orally or parenterally available radioprotective agent that can be made available both before and after radiation injury.